Dilated cardiomyopathy is a multi-factorial disease that includes both the hereditary and acquired forms of cardiomyopathy. Recent experiments have shown that hereditary cardiomyopathy in humans can be associated with genetic defects in components of the dystrophin-glycoprotein complex. For example, mutations in the dystrophin gene lead to a high incidence of cardiomyopathy in Duchenne and Becker muscular dystrophy, and can caused X-linked dilated cardiomyopathy. Mutations in the genes for the sarcoglycans are responsible for limb girdle muscular dystrophy and are often quite associated with cardiomyopathy. In addition, our preliminary data links an acquired form of cardiomyopathy, enteroviral infection, with disruption of the dystrophin-glycoprotein complex. Thus, evidence is accumulating that the dystrophin-glycoprotein complex has a critical role in the genesis of hereditary and acquired cardiomyopathy. Dystroglycan is a key component of the dystrophin- glycoprotein complex that links the cytoskeletal protein dystrophin to the extracellular matrix protein laminin-2. Recent experiments with dystroglycan null ES cells have demonstrated that dystroglycan is required for basement membrane assembly but not cardiac myocyte differentiation. Sarcoglycans interact closely with dystroglycan and recent studies of sarcoglycan null mice have suggested that the underlying mechanism of sarcoglycan related cardiomyopathy is due to the dysfunction of vascular smooth muscle. The overall goal of this project is to test the hypothesis that the dysfunction of the dystrophin-glycoprotein complex can lead to dilated to dilated cardiomyopathy. We plan to test the following three hypotheses: 1) disruption of dystroglycan in the cardiac myocyte is sufficient to disrupt normal basement membrane assembly and induce cardiomyopathy; 2) disruption of sarcoglycan function in the vascular smooth muscle is sufficient and necessary to induce the cardiomyopathy that occurs with genetic alteration of the vascular smooth muscle is sufficient and necessary to induce the cardiomyopathy; 2) disruption of sarcoglycan function in the vascular smooth muscle is sufficient and necessary to induce the cardiomyopathy that occurs with genetic alteration of the sarcoglycan complex; and 3) cleavage of dystrophin in the cardiac myocyte contributes significantly to to the cardiomyopathy of enteroviral infection. To directly examine dystroglycan's function in the heart we have proposed experiments in the first specific aim to circumvent the early lethality of dystroglycan null mutation in order to analyze dystroglycan's role in cardiac basement membrane assembly and cardiac function.. The second aim is to investigate the regulation of the dystroglycan complex by the sarcoglycans in vascular smooth muscle of the heart. For this aim mice with a specific deficiency in delta-sarcoglycan in smooth muscle will be produced. Specific aims three and four identify the mechanisms of enteroviral protease 2A mediated cleavage of dystrophin and determine the significance of this cleavage in the intact heart. The complimentary approach is outlined in these specific aims will yield a new understanding of the role of dystrophin-glycoprotein complex in both hereditary and acquired cardiomyopathy.